The purpose of this project is to study the action of diphtheria toxin at the cellular and molecular level. Our major objectives include: 1) identification and characterization of toxin-specific receptor sites and determination of the mechanism by which diphtheria toxin is activated and enters cells, 2) determination of the cellular and molecular basis for the resistance to diphtheria toxin found in some cells and animal species, 3) elucidation of steps which lead to inhibition of protein synthesis in intoxicated cells, with consideration of whether inhibition of aminoacyl transferase II enzyme is the sole cause of cell destruction and death, 4) extension of our study to include the interaction of other biologically active agents with cells. Investigations will be conducted using cultured mammalian cells and cell- free sytems. A unique opportunity for investigation of both sensitivity and resistance to toxin is presented by isolation in our laboratory of strains of human cells which are resistant to toxin and to certain viruses, as well. Information gained from models using established cell lines will ultimately be extended to differentiated primary cells and animal tissues.